Amide enolate additions to acylsilanes: In situ generation of unusual and stereoselective homoenolate equivalents

Article abstract of DOI:10.1021/ja808811u

The synthesis of β-hydroxy carbonyl compounds is an important goal due to their prevalence in bioactive molecules. A novel approach to construct these structural motifs involves the multicomponent reaction of acylsilanes, amides, and electrophiles. The ad

Full text of DOI:10.1021/ja808811u

Published on Web 06/08/2009
Amide Enolate Additions to Acylsilanes: In Situ Generation of
Unusual and Stereoselective Homoenolate Equivalents
Robert B. Lettan II, Chris V. Galliford,‡ Chase C. Woodward, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
Received November 17, 2008; E-mail: scheidt@northwestern.edu
Abstract: The synthesis of ꢀ-hydroxy carbonyl compounds is an important goal due to their prevalence in bioactive
molecules. A novel approach to construct these structural motifs involves the multicomponent reaction of acylsilanes,
amides, and electrophiles. The addition of amide enolates to acylsilanes generates ꢀ-silyloxy homoenolate reactivity
by undergoing a 1,2-Brook rearrangement. These unique nucleophiles formed in situ can then undergo addition to
alkyl halides, aldehydes, ketones, and imines. The γ-amino-ꢀ-hydroxy amide products derived from the addition of
these homoenolates to N-diphenylphosphinyl imines are generated with excellent diastereoselectivity (g20:1) and
can be efficiently converted to highly valuable γ-lactams. Finally, the use of optically active amide enolates delivers
ꢀ-hydroxy amide products with high levels of diastereoselectivity (g10:1).
Introduction
philes to deliver tertiary ꢀ-hydroxy amides (8) in good yields and
with high levels of stereoselectivity when chiral acetamides are
used.
In 1962, Nickon and Lambert reported the first examples of
homoenolate anion formation (eq 1).1 Optically active camphe-
nilone (1), which has no enolizable protons by classical reactivity
standards, underwent racemization at elevated temperatures in the
presence of potassium tert-butoxide. This loss of optical purity can
best be attributed to the formation of an active homoenolate
intermediate (2/4). Homoenolates are unusual nucleophiles that
differ from enolates in that the negative charge is located on the
ꢀ-carbon of a carbonyl system. These species are therefore less
stable and more difficult to generate than the corresponding enolates
due to the lack of resonance stabilization. In spite of this notable
observation being almost half a century ago, researchers have been
challenged in finding controllable and useful homoenolate equiva-
lents for organic transformations.
Conceptually, the addition of a homoenolate species to an
electrophile is the polarity reversal, or Umpolung2 approach to a
standard conjugate addition. This report describes the utilization
of amide enolate additions to acylsilanes, accessing ꢀ-hydroxy-
substituted homoenolate equivalents through a Brook rearrangement
reaction pathway (eq 2).3 We have found that the intermediate
ꢀ-silyloxy homoenolates (7) undergo smooth addition to electro-
Following Nickons’s seminal discovery of homoenolate
formation, there have been multiple strategies to access ho-
moenolate equivalents (eqs 3-9). The first general method for
the generation and utilization of this unique reactivity pattern
involved the use of acetal-masked Grignard reagents.4 These
‡ Current address: Schering-Plough Research Institute, 2015 Galloping
Hill Rd., Kenilworth, NJ 07033.
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A R T I C L E S
Lettan et al.
reactions, while simultaneously avoiding undesired intramo-
lecular cyclopropanation. Recently, a new approach to ho-
moenolate generation involving nucleophilic N-heterocyclic
carbene (NHC)-catalyzed processes has been independently
investigated by several researchers, including Glorius,17,18
Bode,19,20 Nair,21,22 Zeitler,23 and our group.24,25 For example,
we recently reported the highly stereoselective formal [3 + 3]
cycloaddition of enals (26) and azomethine imines (27),
catalyzed by the carbene generated in situ from benzimidazolium
salt 28 (eq 9).25
Acylsilanes and the Brook Rearrangement. From the com-
mendable contributions from Brook, it has been known that the
addition of organometallic nucleophiles to acylsilanes typically
induces a reversible 1,2-silyl group migration from carbon to
oxygen (eq 10).26 In the 1,2-Brook rearrangement process,
nucleophilic (M-R2) addition to acylsilane 31 yields silyl
alkoxide intermediate 32, which is proposed to undergo revers-
ible and stereospecific rearrangement via silyl epoxide transition
state 33 (or intermediate, not clearly distinguished) to generate
silyloxy carbanion 34. The proposed highly ordered cyclic silyl
epoxide transition state is supported by very large negative
entropies of activation (∆S‡ ) -35 to -45 cal/K).3 Overall,
the unique reactivity of acylsilanes enables them to possess
sequential electrophilic/nucleophilic character at the same carbon
position. The additions of alkynyl lithium reagents or alkenyl
Grignard reagents to acylsilanes trigger this rearrangement to
access useful silyloxy carbanions.27-30 The addition of enolates
to acylsilanes has received much less attention in comparison
to other organometallic nucleophiles.31,32 If developed ef-
fectively, this method for bond construction is an alternative
for the difficult analogous reaction involving the direct asym-
metric addition of enolates to ketones.33-38
homoenolate equivalents (9) have been used in 1,2-addition
reactions to carbonyl compounds (eq 3), acylations, and
conjugate additions. The utility of these reactions has also been
employed in natural product synthesis.5-7 Approximately 20
years following Nickon’s report, Hoppe employed novel
sparteine-carbanion complexes of deprotonated 2-butenyl car-
bamates (12) in enantioselective homoaldol reactions (eq 4).8-10
Beak later reported a related approach with allyl amines (15),
which after hydrolysis, provides the corresponding ꢀ-substituted
aldehydes (17) in good yield (eq 5).11,12 These systems allow
direct access to homoenolates and provide a manner to control
the absolute stereochemistry of the products. Hauser introduced
the base-induced carboxylation of aryl homoenolates,13 which
has since been successfully applied to the synthesis of several
natural products (eq 6).14 Sakurai introduced a method utilizing
the Lewis acid mediated formation of homoenolates from 3-silyl-
3-siloxypropenes (20, eq 7).15 Nakamura and Kuwajima devel-
oped a similar approach to homoenolate anion reactivity using
silyloxycyclopropanes (23) as a synthon (eq 8).16 In the presence
of zinc(II) chloride, the ring-opening of silyloxycyclopropane
23 occurs readily to provide a stabilized etherate intermediate
(24). Zinc homoenolate 24 reacts with a variety of electrophiles
to undergo synthetically useful carbon-carbon bond-forming
Takeda was the first to report the addition of ketone-derived
enolates to acylsilanes (eq 11).39-42 The addition of lithium
enolate 36 to acylsilane 35 yields electron-delocalized allylic
anion 37, which proceeds through an intramolecular homoaldol
(17) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205–
6208.
(18) Burstein, C.; Tschan, S.; Xie, X. L.; Glorius, F. Synthesis 2006, 2418–
2439.
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(2) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239–258.
(3) Brook, A. G. Acc. Chem. Res. 1974, 7, 77–84.
(4) Bal, S. A.; Marfat, A.; Helquist, P. J. Org. Chem. 1982, 47, 5045–
5050.
(19) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
14370–14371.
(20) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873–3876.
(21) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc.
2006, 128, 8736–8737.
(5) Buchi, G. W., H. J. Org. Chem. 1969, 34, 1122–1123.
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6517.
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(26) Brook, A. G. Acc. Chem. Res. 1974, 7, 77–84.
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2748.
(8) Hoppe, D.; Lichtenberg, F. Angew. Chem., Int. Ed. 1982, 21, 372.
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9527–9531.
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Amide Enolate Additions to Acylsilanes
A R T I C L E S
addition pathway to provide cyclized silyl enol ether 38.
However, when the acylsilane lacks R,ꢀ-unsaturation, Takeda
observed the major product to be the hydroxy cyclopropane (42,
X ) alkyl, eq 12). This highly substituted carbocycle arises
from the internal attack of the in situ-generated ꢀ-silyloxy
homoenolate (41).
observed (as measured by TLC), and benzyl bromide was added.
This three-component reaction provided ꢀ-hydroxy amide 53
in 86% yield after desilylation.51 Notably, the corresponding
cyclopropane (50) or O-alkylation compound (49) was not
observed. The absence of hydroxy cyclopropanes confirmed our
hypothesis that the reduced electrophilicity of the amide carbonyl
favors intermolecular reactivity. Methods were surveyed for
product desilylation (including multiple fluoride sources and
Brønsted acid), with tetrabutylammonium fluoride giving the
highest yield and reaction rate. Encouraged by these results, a
range of electrophiles was surveyed. Primary, allylic and
benzylic halides all afford the corresponding tertiary alcohols
(53-57) in good yields (entries 1-5). The ꢀ-silyloxy homoeno-
late intermediate also undergoes facile addition to aldehydes
and ketones (entries 6 and 7). In cases where elimination (entry
5) or deprotonation (entry 7) is a possibility, the reaction
proceeds surprisingly without complication. Furthermore, sec-
ondary ꢀ-hydroxy amide 60 is generated by treating the
homoenolate intermediate with acidic methanol (entry 8). While
the free alcohols are easily obtained by exposure of the
unpurified reaction to fluoride (TBAF), it remains difficult to
obtain products with the silyl-protected alcohols in tact even
using mild work up conditions.
We proceeded to examine how this new process is impacted by
different substituents on the acylsilane (Table 2, eq 16). The
optimized reaction proceeds in good yields in the presence of both
electron-deficient (entries 3, 4, and 6) and electron-rich (entry 5)
aromatic systems. However, when acetyltrimethylsilane (66) is
employed, a complex mixture primarily containing the O-alkylation
product (no Brook rearrangement occurs) is recovered (entry 7).
This observation is not surprising since aromatic substitution
stabilizes the ꢀ-silyloxy homoenolate intermediate, promoting the
Brook rearrangement in the previous examples (entries 1-6).
Additionally, the deprotonation of an enolizable acylsilane by the
parent enolate is a potentially competitive process that can interfere
with the normal reaction pathway. Aliphatic dimethylphenyl
acylsilanes have been previously reported to be effective Brook
rearrangement precursors due to the increased stabilization of the
With our interest in developing new nucleophilic species
derived from acylsilanes,43-47 as well as homoenolate equiva-
lents,24,25 we chose to explore the combination of alternative
enolates and acylsilanes to access stable homoenolate intermedi-
ates that could then proceed through the desired intermolecular
addition pathway (eq 13). The success of this single-flask
process depended on controlling the intermediates in the reaction
to favor intermolecular reactivity via the ꢀ-silyloxy homoenolate
(47, eq 14). Due to their decreased electrophilicity in comparison
to ketones, we chose amide enolates (X ) NR2) to potentially
disfavor the intramolecular generation of siloxy cyclopropane
50 and promote intermolecular addition and the formation of
tertiary ꢀ-hydroxy amide 48. The details of this investigation,
including scope, product elaboration, and mechanism, are
reported herein.48,49
Results and Discussion
pentavalent silyloxy anion intermediate (33) from the aromatic
substituent on silicon.52-60 The ꢀ-hydroxy amide products were
not observed when using dimethylphenyl acylsilanes under our
developed reaction conditions (entries 8-9). As an alternative to
aliphatic acylsilanes, tert-butyl trimethylsilylglyoxylate (69)61 did
prove to be effective for this transformation, providing the
γ-carboxy-ꢀ-hydroxy amide (78) in moderate yield (entry 10).
Installation of the tert-butyl ester provides a synthetic handle that
can be potentially further functionalized to access a variety of
functional groups.62
Reaction Development. Our investigation into the use of
enolate additions to acylsilanes as homoenolate equivalents
began by utilizing reactive and readily available starting
materials. The initial reaction was conducted with dimethylac-
etamide (51) and benzoyl trimethylsilane (52),50 with benzyl
bromide as the electrophilic trapping reagent (entry 1, Table 1,
eq 15). Amide enolate formation with lithium diisopropylamine
(LDA) in THF was followed by the addition of acylsilane 52.
After 15 min at -78 °C, disappearance of acylsilane was
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A R T I C L E S
Lettan et al.
Table 1. Reaction with Electrophiles (R-X)a
Table 2. Surveying Acylsilane Compatibilitya
a Acylsilane and electrophile sequentially added to a 0.2 M enolate
solution in THF at -78 °C. Initial silyl ether products treated with
n-Bu4NF in THF prior to purification. b 1:1 mixture of diastereomers.
a See Table 1 for reaction details. b Minor amounts of O-alkylation
Following the development of the multicomponent homoeno-
late addition, investigation was directed toward the development
of a stereoselective variant of this process. Drawing inspiration
from the previously mentioned work of Hoppe9,10 and Beak,11,12
attempts were made to utilize lithium/sparteine-carbanion pairs
to induce enantioselectivity (Scheme 1, eq 17). One limitation
of this process was the necessity of noncoordinating solvent
(e.g., toluene) to promote sparteine complexation. Under these
conditions,63 the reaction rate and yield were greatly diminished,
and no enantioselectivity was observed.64
product observed. c Complex mixture.
Scheme 1. Enantiocontrol by Sparteine Coordination
An alternative method considered for asymmetric induction
involved auxiliary control by the substitution of dimethylac-
etamide with a chiral acetamide (Table 3, eq 18). Cyclic chiral
auxiliaries were primarily considered on the basis of their
rigidity and proven ability as asymmetric control elements. To
this end, N-acyl oxazolidinones 80 and 81 were synthesized
according to the procedures of Evans65 and Davies,66 respec-
tively. Attempts to control the stereochemical outcome of the
multicomponent reaction with these chiral oxazolidinone aux-
iliaries under the established reaction conditions resulted in
complete decomposition of the starting materials (entries 1 and
2). This result is most likely due to inter- or intramolecular
nucleophilic addition of the homoenolate intermediate (86) to
the relatively electrophilic carbamate carbonyl of the oxazoli-
dinone. To circumvent this problem, prolinol derived auxiliary
8267 and Meyers pseudoephedrine auxiliary 8368 were synthe-
sized. However, these auxiliaries proved ineffective under the
utilized reaction conditions (entries 3 and 4). Subsequently,
N-acyl oxazolidines 84 and 85 were synthesized according to
the procedure of Kanemasa.69,70 Addition of the enantiopure
lithium enolate of 84 or 85 to acylsilane 52, followed by addition
of benzyl bromide, afforded the desired carbinols (91 and 92,
after desilylation) with moderate diastereoselectivity under the
established kinetically controlled reaction conditions (-78 °C,
(33) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233–4235.
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Amide Enolate Additions to Acylsilanes
A R T I C L E S
Table 3. Diastereoselective Enolate/Acylsilane Reactionsa
Scheme 2. Homoenolate Conjugate Addition
to 10:1 is achieved (entry 2). Importantly, high levels of
stereoselectivity are also observed when only the initial ho-
moenolate intermediate (86) is warmed to 0 °C for 15 min. This
result suggests that a thermodynamic equilibration at this point
of the reaction generates the most stable/favorable carbanion
intermediate (86), which is the source of the observed increased
stereoselectivity.72
On the basis of the success of our initial investigations, we
decided to explore expansion of the reaction scope. Exhaustive
attempts were made to effect the addition of homoenolate 95
to conjugate acceptors (Scheme 2, eq 20). Several electrophiles
were surveyed for this reaction profile, but unfortunately none
led to the desired 1,4-addition product. Attempted transmeta-
lation of lithium-homoenolate 95 with ZnCl2, facilitated a retro-
Brook process, generating the corresponding alcohol 98 (eq 21).
A small collection of epoxides and aziridines were also surveyed
as potential electrophiles, although no addition to these substrates
was observed.
a Acylsilane and electrophile sequentially added to a 0.2 M enolate
solution in THF. Silyl ether products treated with n-Bu4NF in THF prior
to purification. b Determined by 1H NMR spectroscopy. c Decom-
position. d 2 equiv of LDA, no addition to acylsilane. e No addition to
benzyl bromide.
(39) Takeda, K.; Fujisawa, M.; Makino, T.; Yoshii, E.; Yamaguchi, K.
J. Am. Chem. Soc. 1993, 115, 9351–9352.
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Yamaguchi, K. Synlett 1993, 841–843.
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Table 4. Effect of Temperature on Diastereoselectivitya
(42) Takeda, K.; Tanaka, T. Synlett 1999, 705–708.
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2004, 126, 2314–2315.
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entry
T1 (°C)
T2 (°C)b
T3 (°C)
yield (%)
drc
(47) Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt, K. A. J.
Org. Chem. 2006, 71, 5715–5724.
1
2
3
-78
0
-78
-78
-78
0
-78
80
79
79
3:1
10:1
10:1
0
0
(48) Lettan, R. B.; Reynolds, T. E.; Galliford, C. V.; Scheidt, K. A. J. Am.
Chem. Soc. 2006, 128, 15566–15567.
(49) Lettan, R. B.; Woodward, C. C.; Scheidt, K. A. Angew. Chem., Int.
Ed. 2008, 47, 2294–2297.
a Acylsilane and electrophile sequentially added to a 0.2 M enolate
solution in THF. Silyl ether products treated with n-Bu4NF in THF prior
to purification. b Reaction temperature after consumption of 52 and
(50) Yamamoto, K.; Hayashi, A.; Suzuki, S.; Tsuji, J. Organometallics
1987, 6, 974–979.
c
1
(51) Some desilylation always occurred during work-up/purification.
Treatment with nBu4NF was carried out to ease characterization and
yield determination efforts.
before the addition of R-X. Determined by H NMR spectroscopy.
entries 5 and 6).71 Attempts to improve the selectivity by cooling
the reaction further (-90 °C) decreased the reactivity of the
homoenolate, preventing alkylation (entry 7). Various bases
(KHMDS and LiHMDS), additives (LiCl, HMPA, and TME-
DA), and solvents (THF, Et2O, toluene, and 1:4 THF/toluene)
were investigated, with no observed improvement in yield or
diastereoselectivity. However, when this sequence is carried out
at elevated temperatures (0 °C), the selectivities improved to
>10:1 (entries 8-10).
A further analysis of the effect of temperature on the observed
diastereoselectivity was investigated (Table 4, eq 19). As noted
above, when the entire reaction procedure is carried out at s78
°C, the observed diastereoselectivity for the addition process
to benzyl bromide is 3:1 (entry 1). Conversely, when the entire
reaction is conducted at 0 °C, an increase in diastereoselectivity
(52) Reich, H. J.; Holtan, R. C.; Bolm, C. J. Am. Chem. Soc. 1990, 112,
5609–5617.
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Lettan et al.
Scheme 3. Homoenolate Addition to Imines
Table 5. Synthesis of γ-Hydroxy Amidesa
Another variant of this new strategy involved the addition of
an imine as the electrophilic component (Scheme 3, eq 22).
Addition of homoenolate 47 to imine 99 would permit access
to highly substituted γ-amino-ꢀ-hydroxy amides (100). More
importantly, cyclization of the amide to the corresponding
γ-lactam (101) was envisioned to be accomplished directly upon
removal of the activating group on the imine nitrogen. The
synthesis of γ-lactams73-77 is an important goal due to their
application in the drug-discovery process, as key intermediates
in the preparation of biologically and pharmaceutically relevant
molecules.78 Compounds containing these heterocycles have
direct applications in the treatment of cancer,78-80 fungal
infections,80 epilepsy,81,82 HIV,83,84 neurodegenerative dis-
eases,85 and depression.86
To evaluate the homoenolate addition to imines, we surveyed
compounds with a variety of different activating groups on
nitrogen (Table 5, eq 23). Following homoenolate formation,
a Acylsilane and electrophile added to a 0.1 M enolate solution in
THF at -78 °C. Silyl ether products treated with n-Bu4NF in THF prior
to purification. b Determined by 1H NMR spectroscopy. c Reaction
warmed slowly to 23 °C following addition of the imine. d Reaction
maintained at s78 °C following addition of the imine.
(63) Reactions were conducted both by forming the enolate/homoenolate
in the presence of (-)-sparteine and by introducing sparteine after
homoenolate formation. Various reaction temperatures (-78 to 23
°C) and solvents (toluene, diisopropylether, tert-butylmethyl ether)
were surveyed.
addition of N-benzyl imine 10287 gave the desired γ-amino
amide (105) in modest yield (entry 1). The major side product
of this reaction is the secondary alcohol (60) resulting from
incomplete addition of the intermediate homoenolate to the
imine after a 24 h reaction period. To increase the reactivity of
the imine, N-sulfonylimine 103 was synthesized.88 Exposure
of imine 103 to the established reaction conditions led to the
formation of desired amide (106) in good yield and diastereo-
selectivity (entry 2). In an attempt to further improve these
results, while simultaneously choosing a less robust N-protecting
group, we synthesized N-diphenylphosphinyl imine 104.89
Addition of the homoenolate to imine 104, followed by warming
to ambient temperature, led to an undesired rearrangement
product (not shown, entry 3). Maintaining the reaction temper-
ature at -78 °C following imine addition negated this side
reaction and gave exclusively the desired γ-amino-ꢀ-hydroxy
amide (107) in good yield and with high diastereoselectivity
(>20:1) after desilylation (entry 4).
(64) As determined by chiral HPLC analysis.
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(71) The absolute stereochemistry of ꢀ-hydroxy amide 92, was determined
by single-crystal X-ray diffraction (see Supporting Information). The
absolute stereochemistry of additional ꢀ-hydroxy amides were
assigned by analogy.
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Int. Ed. 2007, 46, 3912–3914.
For our purposes, the N-diphenylphosphinyl functionality
proved to be an optimal choice as an amino protecting group
because of (a) its electron withdrawing properties,90 (b) the steric
magnitude associated with this functionality and its apparent
stereochemical influence, and (c) the ease of removal of this
group under acidic conditions,91 increasing the potential of
concomitant intramolecular cyclization to the γ-lactam. N-
(78) Das Sarma, K.; Zhang, J.; Huang, Y.; Davidson, J. G. Eur. J. Org.
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(81) Reddy, P. A.; Hsiang, B. C. H.; Latifi, T. N.; Hill, M. W.; Woodward,
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(89) Boyd, D. R.; Malone, J. F.; Mcguckin, M. R.; Jennings, W. B.;
Rutherford, M.; Saket, B. M. J. Chem. Soc., Perkin Trans. 2 1988,
1145–1150.
(83) Spaltenstein, A.; Almond, M. R.; Bock, W. J.; Cleary, D. G.; Furfine,
E. S.; Hazen, R. J.; Kazmierski, W. M.; Salituro, F. G.; Tung, R. D.;
Wright, L. L. Bioorg. Med. Chem. Lett. 2000, 10, 1159–1162.
(84) Kazmierski, W. M.; Andrews, W.; Furfine, E.; Spaltenstein, A.;
Wright, L. Bioorg. Med. Chem. Lett. 2004, 14, 5689–5692.
(85) Tang, K.; Zhang, J. T. Neurol. Res. 2002, 24, 473–478.
(86) Rose, G. M.; Hopper, A.; De Vivo, M.; Tehim, A. Curr. Pharm.
Des. 2005, 11, 3329–3334.
(90) Obrien, P. M.; Sliskovic, D. R.; Blankley, C. J.; Roth, B. D.; Wilson,
M. W.; Hamelehle, K. L.; Krause, B. R.; Stanfield, R. L. J. Med.
Chem. 1994, 37, 1810–1822.
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8810 J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009

Amide Enolate Additions to Acylsilanes
A R T I C L E S
Table 6. γ-Lactam Formationa
110), isolating the R-substituted γ-amino-ꢀ-hydroxy amides
(119-121) with excellent levels of diastereoselection (entries
6-8).99
We next turned our attention to exploring the reaction scope
as it applied to the hydrolysis of the N-diphenylphosphinyl
amide and subsequent intramolecular cyclization to form
ꢀ-hydroxy-γ-lactams, in a single efficient operation (Table 8,
eq 26). Various dimethylacetamide-derived γ-amino-ꢀ-hydroxy
amides (R ) H) undergo cyclization in 5 min at 150 °C
(condition A) to afford the corresponding γ-substituted ꢀ-hy-
droxy-γ-lactams in excellent yields and with retention of
stereochemistry (entries 1-4). By decreasing the reaction
temperature (condition B), the cyclization of 2-furyl amide 118
can be obtained without decomposition (entries 5 and 6). The
R-methyl substituted γ-amino-ꢀ-hydroxy amide (119) provides
the desired R-methyl-γ-lactam (127) in high yield with the
higher temperature conditions (A), but with inversion of
stereochemistry at the R-position (entry 7). The lower temper-
ature conditions (B) provide the corresponding R-substituted
ꢀ-hydroxy-γ-lactams in excellent yield with stereochemical
retention (entries 8-10).
Our next goal was to apply the auxiliary controlled process
to control the absolute stereochemistry in the synthesis of highly
substituted ꢀ-hydroxy-γ-lactams (Table 9, eq 27). The use of
chiral acetamide 84 in the homoenolate reaction sequence, with
N-diphenylphosphinyl imine 112 as the electrophile, provides
γ-lactam 124, albeit with no absolute stereochemical control
(entry 1). γ-Amino-ꢀ-hydroxy amide intermediate 130 was not
isolated for these initial selectivity studies to ensure that
enantioselectivity of γ-lactam 124 was not augmented due to
inexact recovery of both diastereomers of amide 130 during
the purification process. Conducting the experiment again with
chiral amide 84, this time with the optimized conditions
requiring “equilibration” at 0 °C following the addition to
acylsilane 52, and prior to addition of imine 112,100 gives
moderate enantioselectivity in the formation of 124 (entry 2).
Continuing with optimization of this homoenolate process, a
similar trend was observed with amide 85 (entries 3 and 4),
ultimately providing 124 with high selectivity (87% ee, entry
4).101 The γ-amino-ꢀ-hydroxy amide intermediate (130) was
also isolated in good yield and high diastereoselectivity.102
Hydrolysis of this sterically hindered oxazolidine auxiliary
typically requires forcing conditions (refluxing 6 M H2SO4 in
AcOH). With our products, hydrolysis of the oxazolidine under
these conditions has led to elimination of the ꢀ-hydroxy
functionality. The microwave irradiation protocol presented
represents a more mild (3 M HCl in THF) and efficient removal
of this auxiliary.
entry
conditions
temp (°C)
time
yield (%)
drb
1
2
3
4
5
6
7
8
9
BF3 ·OEt2/CH2Cl2
Sc(OTf)2/toluened
Zn(OTf)2/toluened
Cu(OTf) toluened
concd HCl/THF
concd HCl/THF
concd HCl/THF
3 M HCl/THF
23
115
115
115
23
24 h
24 h
24 h
24 h
48 h
17 h
5 min
5 min
30 min
0c
0c
-
-
0c
-
0c
-
92
96
98
98
73g
>20:1
>20:1
>20:1
>20:1
>20:1
70e
150f
150f
150f
2 M HCl/THF
a A 0.1-0.5 M solution of the amide in solvent. b Determined by 1H
NMR spectroscopy. c No reaction. d Reaction also conducted in CH2Cl2;
no reaction. e Reflux. f Microwave irradiation. g Not to complete
conversion.
Diphenylphosphinyl imines have been previously used exten-
sively as electrophiles in asymmetric reductions,92-96 vinyl zinc
additions,97 acylanion additions,44 and nucleophilic additions
of arylboronic acids.98
Initial attempts to afford simultaneous deprotection and
cyclization of γ-amino-ꢀ-hydroxy amide 107 to the correspond-
ing γ-lactam (108) under Lewis acidic conditions were unsuc-
cessful, even at refluxing temperatures (entries 1-4, Table 6,
eq 24). Given the precedence for N-diphenylphosphinyl depro-
tection under Brønsted acid conditions,44 the cyclization was
attempted employing hydrochloric acid. There was some
concern that dehydration might occur under acidic conditions
to give either the R,ꢀ- or ꢀ,γ-unsaturated γ-lactams due to the
potential aromatic-stabilized carbocation at the ꢀ-position prior
to conducting this experiment. No elimination is observed, and
desired γ-lactam 108 is recovered in excellent yield at ambient
temperatures, albeit over long reaction times (2 days) and with
large amounts of excess concentrated hydrochloric acid (entry
5). Conducting the reaction at reflux provides notable rate
enhancement, with no product decomposition or elimination of
the ꢀ-hydroxyl group (entry 6). The use of microwave irradiation
promotes the concomitant deprotection and lactam formation
in only 5 min (entry 7), and the concentration of acid could be
reduced (3 M) without loss of reactivity (entry 8).
An examination of the imine scope for the formation of
γ-amino-ꢀ-hydroxy amides (Table 7, eq 25) demonstrates that
the reaction proceeds in good yields in the presence of both
electron-deficient (entries 2 and 3) and electron-rich (entries 4
and 5) aromatic systems. A third substituent is successfully
incorporated through the use of R-substituted amides (109 and
Mechanistic Details. The general mechanism for the enolate
addition to acylsilanes presumably proceeds through a Brook
rearrangement-mediated pathway (Scheme 4, eq 28). Enolate
formation from dimethylacetamide (51) with LDA followed by
addition to the acylsilane (52) provides lithium-alkoxide inter-
mediate 131. This intermediate then undergoes a 1,2-silyl
migration (Brook rearrangement) to provide active carbanion
(92) Krzyzanowska, B.; Stec, W. J. Synthesis 1982, 270–273.
(93) Cote, A.; Boezio, A. A.; Charette, A. B. Proc. Nat. Acad. Sci. U.S.A.
2004, 101, 5405–5410.
(94) Boezio, A. A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 1692–
1693.
(95) Weix, D. J.; Shi, Y. L.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127,
1092–1093.
(99) Relative stereochemistry of 128 determined by 1H NOE NMR
spectroscopy, and further assignments were made by analogy.
(100) See experimental section and Supporting Information for details.
(101) Absolute stereochemistry of 124 determined by X-ray crystallography
of the 4-bromobenzoyl imide of 124, and further assignments were
made by analogy. See Supporting Information for details.
(102) Enantiomeric excess determined by HPLC analysis (chiral stationary
phase) and absolute configuration determined by X-ray crystal-
lography. See Supporting Information for details.
(96) Graves, C. R.; Scheidt, K. A.; Nguyen, S. T. Org. Lett. 2006, 8,
1229–1232.
(97) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2001,
123, 5122–5123.
(98) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima,
T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466–
2467.
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A R T I C L E S
Lettan et al.
Table 7. Synthesis of γ-Hydroxy Amidesa
a Acylsilane and electrophile added to a 0.1 M enolate solution in THF at -78 °C. Silyl ether products treated with n-Bu4NF in THF prior to
b
1
purification. Determined by H NMR spectroscopy.
Table 8. γ-Amino-ꢀ-hydroxy Amidesa
a A 0.1 M solution of the amide in THF/3 M aqueous HCl was heated utilizing microwave irradiation. b Condition A ) 150 °C for 5 min (1:2 THF/3
c
M aqueous HCl); Condition B ) 70 °C for 10 min (1:2 THF/3 M aqueous HCl). Determined by H NMR spectroscopy. d Decomposition.
1
intermediate 132. Suitable electron stabilizing functionality (aryl,
carboxylate) is needed adjacent to this carbanion to perturb the
equilibrium to favor carbanion 132. In this example, addition
of carbanion 132 to benzylbromide proceeds to give ꢀ-hydroxy
amide 53, following desilylation.
The general mechanism can be applied to explain the
diastereoselective homoenolate additions to imines (Scheme 5,
eq 29). The proposed mechanism involves the diastereoselective
addition of the Z-enolate of amide 133 to acylsilane 52 and
subsequent stereospecific 1,2-Brook rearrangement to give
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8812 J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009

Amide Enolate Additions to Acylsilanes
A R T I C L E S
Table 9. Enantioenriched ꢀ-Hydroxy-γ-Lactamsa
is assumed that there is no rotation about the nitrogen and
carbonyl carbon bond given the high energy barrier for this
process. Subsequent stereospecific Brook rearrangement (140)3
rapidly occurs to give internally coordinated diastereomers 86
(major) and 141 (minor). Strongly coordinating additives (e.g.,
DMPU, HMPA) reduce the diastereoselectivity and yield of the
reactions, supporting the proposed internal coordination of the
amide carbonyl to the ꢀ-organolithium substituent. Furthermore,
O-alkylation is not observed when the reactions are conducted
at -78 or 0 °C, suggesting that the Brook rearrangement occurs
rapidly to generate carbanions 86/141. The inverse relationship
of selectivity to temperature suggests that performing the
reaction under thermodynamically controlled conditions (0 °C)
facilitates interconversion of 86/141 prior to alkylation. Since
carbanion 141 is destabilized by nonbonding interactions
between the trimethylsilylether and benzyl group of the auxil-
iary, the reaction preferentially proceeds via thermodynamically
favored intermediate 86, to give the ꢀ-hydroxy amide (130),
followed by desilylation.
Conclusions
a See Tables 6 and 5 for reaction details. b Determined by 1H NMR
spectroscopy. c Determined by HPLC analysis. d Brief equilibration time
at 0 °C following consumption of 52. See Supporting Information for
details. e 92% yield from 130, 63% from 85.
A new strategy has been developed for the synthesis of
tertiary ꢀ-hydroxy amides using ꢀ-silyloxy homoenolates ac-
cessed from amide enolates and acylsilanes. These unconven-
tional nucleophilic species undergo addition to alkyl halides,
aldehydes, ketones, and imines. Amide enolates strongly favor
C-alkylation of the homoenolate over O-alkylation and avoid
the formation of alkoxy cyclopropane products. Homoenolate
addition to imines provides the γ-amino-ꢀ-hydroxy amides in
a single flask operation with good yields and excellent selectivity
for each newly formed stereocenter. The use of microwave
irradiation under acidic conditions promotes hydrolysis and
cyclization to form the corresponding γ-lactams in excellent
yields with retention of stereochemistry. The utilization of chiral
acetamides allows for stereochemical control of the tertiary
alcohol and subsequent γ-lactam products. This novel approach
employing acylsilanes and the power of the 1,2-Brook rear-
rangement to access synthetically useful homoenolate reactivity
is an addition to the increasing number of Umpolung strategies
that lead to potentially useful classes of molecules.
Scheme 4. General Mechanism
Scheme 5. Diastereoselective Addition to Imines
Experimental Section
General Procedure for the Synthesis of ꢀ-Hydroxy Amides.103
To a flame-dried flask under a positive pressure of nitrogen was
added THF (2 mL) and diisopropylamine (0.79 mmol). The solution
was cooled to -78 °C and n-butyllithium (1.5 M in hexanes, 0.73
mmol) was added by syringe. The reaction was warmed to 0 °C,
stirred for 30 min, and then recooled to -78 °C. Dimethylacetamide
(0.84 mmol) was added dropwise to the LDA solution, and the
reaction mixture was warmed to 0 °C. After being stirred at 0 °C
for 1 h, the reaction mixture was cooled to -78 °C and a -78 °C
solution of the acylsilane (0.56 mmol) in THF (0.5 mL) was added
via cannula. The acylsilane delivery flask was rinsed with an
additional portion of THF (0.5 mL), and this rinse was transferred
to the reaction flask. The resulting homogeneous solution was stirred
for 30 min, after which time a solution of the electrophile (1.68
mmol) in THF (0.5 mL) was added via cannula, again rinsing the
delivery flask with an additional portion of THF (0.5 mL). The
reaction mixture was warmed slowly to ambient temperature over
6 h, and then stirred for an additional 6 h at the same temperature.
The reaction was quenched by the addition of saturated aqueous
ammonium chloride and extracted with ethyl acetate (×3). The
internally coordinated carbanion intermediate 136. Electrophilic
approach of imine 104 then occurs by open transition-state 137,
at an orientation that alleviates nonbonding interactions between
the N-diphenylphosphinyl group of the imine and the silyloxy
group of the homoenolate, to yield the γ-amino-ꢀ-hydroxy
amide (107,119,121), with higher diastereoselectivity. The
overall process generates up to three contiguous stereogenic
centers in a single operation with a high degree of control.
On the basis of the known relationship of temperature to
diastereoselectivity and the current understanding of 1,2-silyl
migrations, we have proposed a reaction pathway that accounts
for the observed stereochemistry with chiral amide 85 (Scheme
6, eq 30). The current model for diastereoselection involves
enolate addition to acylsilane 52 through Zimmerman-Traxler
transition state 138, minimizing nonbonding interactions be-
tween the trimethylsilyl group and the auxiliary. This initial
enolate addition is the proposed source of the observed 3:1 ratio
of products under kinetic control (-78 °C). For this model, it
(103) See Supporting Information for revised experimental details as they
pertain to the addition to imines.
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J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009 8813

A R T I C L E S
Lettan et al.
Scheme 6. Auxiliary Controlled Diastereoselective Reactions
combined organic layers were dried (Na2SO4), filtered, and
concentrated. The unpurified silyl ether product was dissolved in
THF (2 mL). To this solution was added tetrabutylammonium
fluoride (1.0 M in THF, 1.68 mmol), and the mixture was stirred
at room temperature for 30 min. The reaction mixture was quenched
by the addition of water, extracted with diethyl ether (×3), dried
(MgSO4), filtered, and concentrated. The resulting residue was
purified by column chromatography on silica gel.
General Procedure for the Preparation of ꢀ-Hydroxy-γ-Lac-
tams. To a solution of the γ-amino-ꢀ-hydroxy amide (0.20 mmol)
in THF (1.0 mL) was added 3 M aqueous HCl (1.0 mL). The
resulting mixture was stirred for 2 min before heating at 150 °C
(or 70 °C) in the microwave for 5-20 min. The resulting mixture
was cooled to ambient temperature, slowly neutralized with solid
sodium bicarbonate (until evolution of gas ceases), and extracted
with dichloromethane. The organic layers were combined, dried
(Na2SO4), filtered, and concentrated. The resulting residue was
purified by column chromatography on silica gel.
General Procedure for the Synthesis of ꢀ-Hydroxy Amides
with Chiral Acetamides.79 To a mixture of calcium sulfate (100
mg, finely ground with a mortar and pestle, and heated in a beaker
at 160 °C for at least 48 h prior to use) and THF (0.5 mL) was
added diisopropylamine (0.37 mmol). The resulting solution was
cooled to -78 °C, and n-butyllithium (1.6 M in hexanes, 0.37
mmol) was added dropwise by syringe. The reaction mixture was
warmed to 0 °C, stirred for 30 min, then cooled to -78 °C. To this
solution of LDA was added a -78 °C solution of 85 (0.37 mmol)
in THF (0.8 mL + 0.2 mL rinse) dropwise by cannulation. The
resulting reaction mixture was warmed to 0 °C and stirred for 1 h.
To the resulting reaction mixture was added a cooled to 0 °C
solution of 52 (0.28 mmol) in THF (0.3 mL) in one portion by
cannula, again rinsing the delivery flask with an additional portion
of THF (0.2 mL). The resulting reaction mixture was stirred at 0
°C for 15 min, monitoring for consumption of 52 by TLC (Rf )
0.67 (10:90 ethyl acetate/hexanes)). The electrophile (0.84 mmol)
was added in one portion by syringe and the reaction mixture was
warmed slowly to ambient temperature over 8 h followed by stirring
for an additional 4 h at ambient temperature. The reaction mixture
was quenched by the addition of saturated aqueous ammonium
chloride (2 mL) and extracted with ethyl acetate (×3). The
combined organic layers were dried (Na2SO4), filtered, and
concentrated. The unpurified silyl ether product was dissolved in
THF (2 mL) and treated with tetrabutylammonium fluoride (1.0 M
in THF, 0.84 mmol). After 30 min, the reaction mixture was
quenched by the addition of water, extracted with ethyl acetate (×3),
dried (MgSO4), filtered, and concentrated. The resulting residue
was purified by column chromatography on silica gel.
Acknowledgment. Financial support has been provided in part
by the NSF (CHE-0348979), the PRF (Type G), the Elizabeth
Tuckerman Foundation (C.V.G.), Northwestern University (Summer
Fellowship to C.C.W.), Abbott Laboratories, Amgen, AstraZeneca,
GlaxoSmithKline, 3M, and Boehringer-Ingelheim. We thank Wack-
er Chemical Corp., Sigma-Aldrich, BASF and FMCLithium for
generously providing reagents, Troy Reynolds (NU) for assistance
with X-ray crystallography, and Professor Regan Thomson (NU)
and Dr. Jeremy Starr for helpful discussions. K.A.S. is a fellow of
the Alfred P. Sloan Foundation and an American Cancer Society
Research Scholar.
Supporting Information Available: Detailed experimental
procedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA808811U
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8814 J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009